Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: Cdc25 is partly nuclear; it shuttles between cytoplasm and nucleus, with nuclear accumulation highest in G2 where it must access its substrate Cdc2. Nuclear localization is supported by direct S. pombe experimental data. Reason: Phylogenetic inference is consistent with direct S. pombe localization data showing Cdc25 in both nucleus and cytoplasm. Supporting Evidence: PMID:10523629 wild-type Cdc25, which localized to both the cytoplasm and the nucleus.
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: Cdc25 is present in the cytoplasm as well as the nucleus; checkpoint and stress signaling drive 14-3-3-dependent cytoplasmic accumulation to sequester Cdc25 away from its nuclear substrate. Reason: Supported by phylogenetic inference and corroborated by direct S. pombe localization data. Supporting Evidence: PMID:15629716 Phosphorylation by Srk1 causes Cdc25 to bind to Rad24, a 14-3-3 protein family member, and accumulation of Cdc25 in the cytoplasm.
GO:0000086 G2/M transition of mitotic cell cycle	IBA GO_REF:0000033	ACCEPT	Summary: Cdc25 acts at the G2/M transition by dephosphorylating Cdc2-Tyr15 to trigger mitotic entry. This is a core process, though the directional term positive regulation of G2/M transition (GO:0010971) more precisely captures Cdc25's activating role. Reason: Cdc25 is the founding mitotic inducer acting at G2/M; well supported by classical genetics. Supporting Evidence: PMID:3955656 the cdc25+ gene function is required to initiate
GO:0010971 positive regulation of G2/M transition of mitotic cell cycle	IBA GO_REF:0000033	ACCEPT	Summary: Core biological process. Cdc25 is a dosage-dependent positive regulator of mitotic entry: increased Cdc25 advances mitosis to a smaller cell size, and it counteracts the inhibitory Wee1 kinase. Reason: This is the central, experimentally established role of Cdc25 as the mitotic inducer counteracting Wee1. Supporting Evidence: PMID:3955656 increased cdc25+ expression causes mitosis to initiate at a reduced cell size. This shows that cdc25+ functions as a dosage-dependent inducer in mitotic control
GO:0110032 positive regulation of G2/MI transition of meiotic cell cycle	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Cdc25 also drives the meiotic G2/MI transition using the same Cdc2-Tyr15 dephosphorylation; its expression in meiosis is induced by Mei4. This is a genuine but non-core role relative to its central mitotic function. Reason: Meiotic involvement is experimentally supported (not an SPKW keyword artifact), but it is a deployment of the same activity in meiosis rather than the primary mitotic function. Supporting Evidence: PMID:17804800 Forced dephosphorylation of Cdc2p on tyrosine-15 thus induced meiosis I in mei4 mutant cells without a delay
GO:0004725 protein tyrosine phosphatase activity	IEA GO_REF:0000120	ACCEPT	Summary: Core molecular function. Cdc25 is a protein tyrosine phosphatase (EC 3.1.3.48) that dephosphorylates Cdc2-Tyr15; the IEA mapping is fully consistent with direct experimental evidence. Reason: Strongly supported by direct biochemical and genetic data demonstrating tyrosine phosphatase activity toward Cdc2. Supporting Evidence: PMID:1756737 GST-cdc25) caused tyrosyl dephosphorylation and activation of immunoprecipitated p34cdc2
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: Nuclear localization mapped from UniProt Subcellular Location vocabulary; consistent with direct S. pombe data showing Cdc25 accumulates in the nucleus, highest in G2. Reason: Concordant with experimental localization evidence. Supporting Evidence: PMID:10523629 wild-type Cdc25, which localized to both the cytoplasm and the nucleus.
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: Cytoplasmic localization mapped from UniProt Subcellular Location vocabulary; consistent with the experimentally observed cytoplasm/nucleus distribution and 14-3-3-driven cytoplasmic sequestration. Reason: Concordant with experimental localization evidence. Supporting Evidence: PMID:10523629 wild-type Cdc25, which localized to both the cytoplasm and the nucleus.
GO:1902751 positive regulation of cell cycle G2/M phase transition	IEA GO_REF:0000002	MODIFY	Summary: InterPro2GO term that is essentially equivalent to GO:0010971 (positive regulation of G2/M transition of mitotic cell cycle), which is more specific and already directly supported. Redundant with the mitotic-specific term. Reason: The mitotic-specific child term GO:0010971 is preferred over this more general cell cycle phase transition term. Proposed replacements: positive regulation of G2/M transition of mitotic cell cycle Supporting Evidence: PMID:3955656 cdc25+ functions as a dosage-dependent inducer in mitotic control
GO:0004725 protein tyrosine phosphatase activity	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity transfer of protein tyrosine phosphatase activity; redundant with the strong direct IDA evidence in S. pombe but correct. Reason: Correct function, directly demonstrated experimentally in S. pombe. Supporting Evidence: PMID:1756737 cdc25 proteins directly dephosphorylate and activate p34cdc2 kinase to induce M-phase
GO:0031569 mitotic G2 cell size control checkpoint signaling	IMP PMID:28479325 Size-Dependent Expression of the Mitotic Activator Cdc25 Sug...	ACCEPT	Summary: Size-dependent expression of Cdc25 provides a cell-size control mechanism: smaller cells make less Cdc25 and larger cells more, so cells trigger division when Cdc25 reaches a threshold concentration. A bona fide core-related role in coupling cell size to mitotic entry. Reason: Directly supported by the cited study demonstrating size-dependent Cdc25 expression as a size-control mechanism. Supporting Evidence: PMID:28479325 cdc25 transcript levels are regulated such that smaller cells express less Cdc25 and larger cells express more Cdc25, creating an increasing concentration of Cdc25 as cells grow and providing a mechanism for cells to trigger cell division when they reach a threshold concentration of Cdc25
GO:0004725 protein tyrosine phosphatase activity	IMP PMID:9042863 Cdc2 tyrosine phosphorylation is required for the DNA damage...	ACCEPT	Summary: This paper shows the DNA damage checkpoint G2 arrest depends on inhibitory Cdc2-Tyr15 phosphorylation and that the rate of Cdc2 tyrosine dephosphorylation (mainly via Cdc25) is reduced by irradiation. It supports Cdc25 acting as the Cdc2 tyrosine dephosphorylating activity in the checkpoint context but is not a direct enzymatic assay of Cdc25 PTP activity. The molecular function itself is better and more directly supported by IDA references. Reason: Function is correct (Cdc25 is the Cdc2 tyrosine phosphatase) and the cited work is consistent, though this is genetic/indirect; stronger IDA evidence exists. Supporting Evidence: PMID:9042863 the rate of Cdc2 tyrosine dephosphorylation is reduced by irradiation. This result implicates regulation of Cdc2 tyrosine dephosphorylation, mainly carried out by the Cdc25 tyrosine phosphatase
GO:0110044 regulation of cell cycle switching, mitotic to meiotic cell cycle	IMP PMID:17804800 Mei4p coordinates the onset of meiosis I by regulating cdc25...	KEEP AS NON CORE	Summary: cdc25 is a key Mei4 target controlling entry into meiosis I; forced Cdc2-Tyr15 dephosphorylation bypasses the mei4 arrest. Cdc25 thus contributes to the transition into the meiotic program. A genuine non-core meiotic role. Reason: Experimentally supported meiotic involvement, but secondary to the core mitotic function. Supporting Evidence: PMID:17804800 cdc25+ is an important target of Mei4p in control of entry into meiosis I
GO:0004721 phosphoprotein phosphatase activity	IDA PMID:22665807 Multisite phosphoregulation of Cdc25 activity refines the mi...	MODIFY	Summary: Broad parent term for phosphatase activity. Cdc25 is specifically a protein tyrosine phosphatase (GO:0004725); the more specific term should be used. The cited paper concerns Cdk1/Clp1 phosphoregulation of Cdc25 catalytic activation rather than a new substrate specificity. Reason: The specific tyrosine phosphatase term is more informative than the general phosphoprotein phosphatase activity term. Proposed replacements: protein tyrosine phosphatase activity Supporting Evidence: PMID:22665807 Cdc25 hyperphosphorylation by Cdk1 governs Cdc25 catalytic activation
GO:0005634 nucleus	IDA PMID:18272791 Activation of Srk1 by the mitogen-activated protein kinase S...	ACCEPT	Summary: Direct S. pombe evidence; Srk1 negatively regulates the cycle by inhibiting Cdc25 and driving its nucleus-to-cytoplasm relocation, consistent with a nuclear pool of Cdc25 acting on Cdc2. Reason: Supported by direct experimental localization in S. pombe. Supporting Evidence: PMID:18272791 activation of Srk1 kinase, which negatively regulates cell cycle progression by inhibiting Cdc25
GO:0005829 cytosol	IDA PMID:18272791 Activation of Srk1 by the mitogen-activated protein kinase S...	ACCEPT	Summary: Cytosolic pool of Cdc25 consistent with Srk1/14-3-3-dependent cytoplasmic sequestration. Direct S. pombe evidence. Reason: Supported by direct experimental localization in S. pombe. Supporting Evidence: PMID:18272791 activation of Srk1 kinase, which negatively regulates cell cycle progression by inhibiting Cdc25
GO:0004725 protein tyrosine phosphatase activity	IDA PMID:1703321 Complementation of the mitotic activator, p80cdc25, by a hum...	ACCEPT	Summary: Direct demonstration that Tyr15 dephosphorylation activates the Cdc2-cyclin complex and that a human PTPase substitutes for p80cdc25, reinforcing the tyrosine phosphatase identity of Cdc25. Core molecular function. Reason: Direct evidence for tyrosine phosphatase activity in the Cdc2 activation pathway. Supporting Evidence: PMID:1703321 dephosphorylation of Tyr15 triggered activation of the pp34-cyclin complex from fission yeast, that a human protein-tyrosine phosphatase can catalyze this event both in vitro and in vivo
GO:0010971 positive regulation of G2/M transition of mitotic cell cycle	IMP PMID:1703321 Complementation of the mitotic activator, p80cdc25, by a hum...	ACCEPT	Summary: Cdc25 (and the complementing human PTPase) positively regulates mitotic entry via Cdc2-Tyr15 dephosphorylation. Core process, well supported. Reason: Directly supports Cdc25's positive role in the G2/M transition. Supporting Evidence: PMID:1703321 The complementary DNA that encoded the tyrosine phosphatase replaced the mitotic activator p80cdc25, closely associating the cdc25(+)-activating pathway with tyrosine dephosphorylation of pp34.
GO:0072435 response to mitotic G2 DNA damage checkpoint signaling	IMP PMID:9278510 Cdc25 mitotic inducer targeted by chk1 DNA damage checkpoint...	ACCEPT	Summary: Cdc25 is the direct target of the Chk1 DNA damage checkpoint kinase (and not Wee1); Chk1 associates with and phosphorylates Cdc25 to restrain mitosis after damage. Core checkpoint-related function as the regulated node. Reason: Strong genetic and biochemical evidence that Cdc25 is the effector target of the G2 DNA damage checkpoint. Supporting Evidence: PMID:9278510 These findings identify Cdc25, but not Wee1, as a target of the DNA damage checkpoint
GO:0005515 protein binding	IPI PMID:9278510 Cdc25 mitotic inducer targeted by chk1 DNA damage checkpoint...	MARK AS OVER ANNOTATED	Summary: Bare protein binding referring to the Cdc25-Chk1 interaction (Chk1 is the checkpoint kinase acting on Cdc25). Uninformative as a molecular function; the functional content is captured by the DNA damage checkpoint BP term. Reason: Per curation guidelines, bare protein binding is uninformative; the relevant biology (Cdc25 as a Chk1 substrate/target) is better represented by checkpoint process terms. Supporting Evidence: PMID:9278510 Cdc25 associated with Chk1 in vivo and was phosphorylated when copurified in Chk1 complexes
GO:0005515 protein binding	IPI PMID:9774107 Replication checkpoint requires phosphorylation of the phosp...	MODIFY	Summary: Bare protein binding covering the Cds1/Chk1 and Rad24 (14-3-3) interactions. The 14-3-3 interaction is functionally important and is better represented by the specific term 14-3-3 protein binding (GO:0071889). Reason: Replace uninformative protein binding with the specific 14-3-3 protein binding term that captures the checkpoint-relevant interaction with Rad24. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:9774107 Phosphorylation of Cdc25 promotes its binding to 14-3-3 proteins, preventing it from activating Cdc2
GO:0005515 protein binding	IPI PMID:10523629 DNA damage and replication checkpoints in fission yeast requ...	MODIFY	Summary: Bare protein binding referring to the Cdc25-Rad24 (14-3-3) interaction that mediates checkpoint-dependent nuclear exclusion. The specific term 14-3-3 protein binding is more informative. Reason: Replace uninformative protein binding with 14-3-3 protein binding, capturing the functionally characterized Rad24 interaction. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:10523629 Nuclear exclusion of wild-type Cdc25 was observed upon overproduction of Rad 24, one of the two fission yeast 14-3-3 proteins
GO:0110032 positive regulation of G2/MI transition of meiotic cell cycle	IMP PMID:25492408 Meiotic nuclear movements in fission yeast are regulated by ...	KEEP AS NON CORE	Summary: Cdc25 triggers entry into meiotic nuclear divisions by activating CDK, downstream of the replication checkpoint and independently of Mei4 once expressed. A real non-core meiotic role using the core Cdc2-activating activity. Reason: Experimentally supported meiotic role, secondary to the core mitotic function. Supporting Evidence: PMID:25492408 Mei4 is also required for the expression of phosphatase Cdc25, which activates cyclin-dependent kinase (CDK), and is thereby essential for triggering meiotic nuclear divisions
GO:0004725 protein tyrosine phosphatase activity	IDA PMID:1464318 Pyp3 PTPase acts as a mitotic inducer in fission yeast.	ACCEPT	Summary: This paper characterizes Pyp3 as a second PTPase that cooperates with p80cdc25 to dephosphorylate Cdc2-Tyr15; it confirms cdc25 is a protein tyrosine phosphatase but the direct enzymatic data are on Pyp3, not Cdc25. The MF assignment to Cdc25 is correct but more directly supported by other references. Reason: Function is correct (Cdc25 is the major Cdc2 PTPase); strongest direct evidence is in other references. Supporting Evidence: PMID:1464318 the actions of the p107wee1 tyrosine kinase and p80cdc25 protein tyrosine phosphatase (PTPase)
GO:0005515 protein binding	IPI PMID:11812792 Solution NMR study of the monomeric form of p13suc1 protein ...	MARK AS OVER ANNOTATED	Summary: Bare protein binding linked to an NMR structural study of p13suc1/CKS. The paper is about Suc1 structure and does not substantively characterize a functional Cdc25-Suc1 interaction; uninformative and peripheral for Cdc25. Reason: Bare protein binding is uninformative, and the cited reference is a Suc1 structural study rather than a characterization of a Cdc25 interaction. Supporting Evidence: PMID:11812792 Cyclin-dependent kinase subunit (CKS) proteins bind to cyclin-dependent kinases and target various proteins to phosphorylation and proteolysis during cell division
GO:0005634 nucleus	IDA PMID:15629716 Inactivation of the Cdc25 phosphatase by the stress-activate...	ACCEPT	Summary: Direct S. pombe evidence that Cdc25 localizes to the nucleus (and cytoplasm), with Srk1/14-3-3 controlling its compartmentalization. Nuclear pool is where Cdc25 activates Cdc2. Reason: Supported by direct experimental localization in S. pombe. Supporting Evidence: PMID:15629716 Phosphorylation by Srk1 causes Cdc25 to bind to Rad24, a 14-3-3 protein family member, and accumulation of Cdc25 in the cytoplasm.
GO:0005737 cytoplasm	IDA PMID:15629716 Inactivation of the Cdc25 phosphatase by the stress-activate...	ACCEPT	Summary: Direct S. pombe evidence for a cytoplasmic pool of Cdc25, increased upon Srk1 phosphorylation and 14-3-3 (Rad24) binding. Reason: Supported by direct experimental localization in S. pombe. Supporting Evidence: PMID:15629716 Phosphorylation by Srk1 causes Cdc25 to bind to Rad24, a 14-3-3 protein family member, and accumulation of Cdc25 in the cytoplasm.
GO:0031573 mitotic intra-S DNA damage checkpoint signaling	IMP PMID:15297457 On the slowing of S phase in response to DNA damage in fissi...	ACCEPT	Summary: The intra-S DNA damage checkpoint (Rad3-Cds1 pathway) acts on Cdc2, with Cdc25 regulation contributing to S-phase slowing. Cdc25 participates as the regulated Cdc2 activator. Keep as a checkpoint-related role. Reason: Cdc25 is part of the intra-S checkpoint response acting through Cdc2 regulation. Supporting Evidence: PMID:15297457 a major downstream target of this pathway is the cyclin-dependent kinase, Cdc2
GO:0010971 positive regulation of G2/M transition of mitotic cell cycle	IMP PMID:2665944 Regulation of p34cdc2 protein kinase during mitosis.	ACCEPT	Summary: The cdc25+ gene product activates the p34cdc2 protein kinase to initiate mitosis, the canonical positive regulation of the G2/M transition. Core process. Reason: Directly supports Cdc25's positive role in mitotic initiation. Supporting Evidence: PMID:2665944 the cdc25+ gene product activating the p34cdc2 protein kinase leading to mitotic initiation
GO:0004725 protein tyrosine phosphatase activity	IDA PMID:1756737 p80cdc25 mitotic inducer is the tyrosine phosphatase that ac...	ACCEPT	Summary: Definitive demonstration that p80cdc25 is the tyrosine phosphatase that dephosphorylates and activates p34cdc2, with active-site Cys480 essential. Core molecular function with the strongest direct evidence. Reason: Direct biochemical evidence (tyrosyl dephosphorylation, PTPase properties, catalytic cysteine mutation) for Cdc25 PTP activity. Supporting Evidence: PMID:1756737 Mutation of the cdc25 Cys480 codon, corresponding to an essential cysteine in the active site of PTPases, abolished the phosphatase activity of GST-cdc25
GO:0005829 cytosol	HDA PMID:16823372 ORFeome cloning and global analysis of protein localization ...	ACCEPT	Summary: High-throughput YFP-based localization places Cdc25 in the cytosol, consistent with its known cytoplasmic/nuclear shuttling. Lower-resolution evidence but concordant with focused studies. Reason: Genome-wide localization data consistent with the experimentally established cytoplasm/nucleus distribution. Supporting Evidence: PMID:15629716 accumulation of Cdc25 in the cytoplasm.
GO:0008361 regulation of cell size	NAS GO_REF:0000051	MODIFY	Summary: Cdc25 regulates the cell size at which division occurs (dosage-dependent mitotic inducer; size-dependent expression). The more specific term mitotic G2 cell size control checkpoint signaling (GO:0031569), already annotated with IMP, better captures the mechanism. Reason: A more specific, experimentally supported size-control checkpoint term is available; replace the general cell-size term. Proposed replacements: mitotic G2 cell size control checkpoint signaling Supporting Evidence: PMID:28479325 smaller cells express less Cdc25 and larger cells express more Cdc25
GO:0004725 protein tyrosine phosphatase activity	IDA PMID:1819507 cdc25 M-phase inducer.	ACCEPT	Summary: p80cdc25 directly dephosphorylates Tyr-15 of p34cdc2; supports the core tyrosine phosphatase activity. Concordant with other direct evidence. Reason: Direct evidence for Cdc25-mediated Cdc2-Tyr15 dephosphorylation. Supporting Evidence: PMID:1819507 p80cdc25 encodes a phosphate that acts by directly dephosphorylating the Tyr-15 residue of p34cdc2
GO:0005634 nucleus	IDA PMID:1500423 cdc25 is a nuclear protein expressed constitutively througho...	ACCEPT	Summary: This study characterizes the MAMMALIAN cdc25 protein in nontransformed fibroblasts (nuclear during interphase), not the S. pombe protein. The localization is therefore heterologous/orthology-based support rather than direct S. pombe evidence, but it is consistent with the native nuclear pool. Reason: Nuclear localization is consistent with direct S. pombe data; however the cited reference is mammalian, so it provides only orthologous (ISS-like) support. Supporting Evidence: PMID:1500423 cdc25 protein is found essentially localized in the nucleus throughout interphase and during early prophase
GO:0005737 cytoplasm	IDA PMID:1500423 cdc25 is a nuclear protein expressed constitutively througho...	ACCEPT	Summary: Mammalian cdc25 redistributes to the cytoplasm around nuclear envelope breakdown in fibroblasts; this is heterologous evidence transferred to the S. pombe protein. Native S. pombe data independently support a cytoplasmic pool, so the term is acceptable though the cited reference is mammalian. Reason: Cytoplasmic localization is supported by direct S. pombe data; the cited reference is mammalian and thus orthology-based. Supporting Evidence: PMID:1500423 cdc25 proteins are redistributed throughout the cytoplasm
GO:0010971 positive regulation of G2/M transition of mitotic cell cycle	IMP PMID:3955656 cdc25+ functions as an inducer in the mitotic control of fis...	ACCEPT	Summary: The original genetic identification of cdc25+ as a dosage-dependent mitotic inducer counteracting Wee1. Core process, foundational evidence. Reason: Foundational genetic evidence establishing Cdc25 as the positive regulator of mitotic entry. Supporting Evidence: PMID:3955656 cdc25+ functions to counteract the activity of the mitotic inhibitor wee1+

Core Functions

Protein tyrosine phosphatase that dephosphorylates Cdc2 (CDK1) on the inhibitory Tyr15 residue, activating the Cdc2-cyclin (Cdc13) kinase to trigger entry into mitosis. This is the rate-limiting, dosage-dependent step of the G2/M transition and is the positive counterpart to the Wee1/Mik1 inhibitory kinases.

Molecular Function:

protein tyrosine phosphatase activity

Directly Involved In:

positive regulation of G2/M transition of mitotic cell cycle G2/M transition of mitotic cell cycle

Cellular Locations:

nucleus cytosol

Supporting Evidence:

PMID:1756737
cdc25 proteins directly dephosphorylate and activate p34cdc2 kinase to induce M-phase
PMID:3955656
cdc25+ functions as a dosage-dependent inducer in mitotic control

Central effector node of the DNA replication, DNA damage, and stress-activated checkpoints: checkpoint kinases (Chk1, Cds1) and the SAPK-activated Srk1 kinase phosphorylate Cdc25 to create 14-3-3 (Rad24/Rad25) binding sites, inhibiting Cdc25 and excluding it from the nucleus, thereby delaying mitotic entry until DNA is intact and replicated.

Molecular Function:

14-3-3 protein binding

Directly Involved In:

response to mitotic G2 DNA damage checkpoint signaling mitotic intra-S DNA damage checkpoint signaling

Cellular Locations:

cytoplasm

Supporting Evidence:

PMID:9278510
These findings identify Cdc25, but not Wee1, as a target of the DNA damage checkpoint
PMID:10523629
14-3-3 binding to Cdc25 is required for fission yeast cells to arrest their cell cycle in response to DNA damage and replication blocks.

Size-dependent mitotic inducer: Cdc25 abundance scales with cell size so that the rising Cdc25 concentration couples cell growth to the timing of division, contributing to cell-size homeostasis at the G2/M transition.

Molecular Function:

protein tyrosine phosphatase activity

Directly Involved In:

mitotic G2 cell size control checkpoint signaling

Supporting Evidence:

PMID:28479325
cdc25 transcript levels are regulated such that smaller cells express less Cdc25 and larger cells express more Cdc25, creating an increasing concentration of Cdc25 as cells grow

References

file:interpro/panther/PTHR10828/PTHR10828-review.md

PANTHER family review PTHR10828: IBA propagation assessment for cdc25

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000051

S. pombe keyword mapping

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10523629

DNA damage and replication checkpoints in fission yeast require nuclear exclusion of the Cdc25 phosphatase via 14-3-3 binding.

14-3-3 (Rad24/Rad25) binding keeps Cdc25 out of the nucleus and is required for DNA damage and replication checkpoint arrest; wild-type Cdc25 localizes to both nucleus and cytoplasm and shuttles between them.

"Nuclear exclusion of wild-type Cdc25 was observed upon overproduction of Rad 24, one of the two fission yeast 14-3-3 proteins, indicating that one function of Rad 24 is to keep Cdc25 out of the nucleus."

PMID:11812792

Solution NMR study of the monomeric form of p13suc1 protein sheds light on the hinge region determining the affinity for a phosphorylated substrate.

Structural study of p13suc1/CKS; does not substantively characterize a Cdc25 interaction, so the Cdc25 protein-binding annotation derived from it is peripheral.

"Cyclin-dependent kinase subunit (CKS) proteins bind to cyclin-dependent kinases and target various proteins to phosphorylation and proteolysis during cell division"

PMID:1464318

Pyp3 PTPase acts as a mitotic inducer in fission yeast.

p80cdc25 is the major protein tyrosine phosphatase dephosphorylating Cdc2-Tyr15; Pyp3 cooperates as a second PTPase.

"the actions of the p107wee1 tyrosine kinase and p80cdc25 protein tyrosine phosphatase (PTPase)"

PMID:1500423

cdc25 is a nuclear protein expressed constitutively throughout the cell cycle in nontransformed mammalian cells.

Mammalian cdc25 is nuclear during interphase and redistributes to the cytoplasm at nuclear envelope breakdown; this is heterologous evidence relative to S. pombe cdc25.

"cdc25 protein is found essentially localized in the nucleus throughout interphase and during early prophase"

PMID:15297457

On the slowing of S phase in response to DNA damage in fission yeast.

The Rad3-Cds1 intra-S DNA damage checkpoint acts through Cdc2, the kinase whose Tyr15 dephosphorylation is controlled by Cdc25.

"a major downstream target of this pathway is the cyclin-dependent kinase, Cdc2"

PMID:15629716

Inactivation of the Cdc25 phosphatase by the stress-activated Srk1 kinase in fission yeast.

Srk1 (downstream of Sty1/Spc1) inhibits Cdc25 during the normal cycle and under non-genotoxic stress by phosphorylating it at the Chk1/Cds1 sites, promoting Rad24 (14-3-3) binding and cytoplasmic accumulation.

"Srk1 interacts with and phosphorylates Cdc25 at the same sites phosphorylated by the Chk1 and Cds1 (Chk2) kinases"

PMID:16823372

ORFeome cloning and global analysis of protein localization in the fission yeast Schizosaccharomyces pombe.

PMID:1703321

Complementation of the mitotic activator, p80cdc25, by a human protein-tyrosine phosphatase.

Cdc2-Tyr15 dephosphorylation triggers activation of the Cdc2-cyclin complex, and a human protein tyrosine phosphatase can substitute for p80cdc25.

"dephosphorylation of Tyr15 triggered activation of the pp34-cyclin complex from fission yeast, that a human protein-tyrosine phosphatase can catalyze this event both in vitro and in vivo"

PMID:1756737

p80cdc25 mitotic inducer is the tyrosine phosphatase that activates p34cdc2 kinase in fission yeast.

p80cdc25 directly dephosphorylates and activates p34cdc2; the active-site Cys480 is essential for phosphatase activity, defining Cdc25 as a novel PTPase subclass.

"Mutation of the cdc25 Cys480 codon, corresponding to an essential cysteine in the active site of PTPases, abolished the phosphatase activity of GST-cdc25"

PMID:17804800

Mei4p coordinates the onset of meiosis I by regulating cdc25+ in fission yeast.

cdc25+ is a key Mei4 target controlling entry into meiosis I; forced Cdc2-Tyr15 dephosphorylation bypasses the mei4 arrest.

"Forced dephosphorylation of Cdc2p on tyrosine-15 thus induced meiosis I in mei4 mutant cells without a delay"

PMID:1819507

cdc25 M-phase inducer.

p80cdc25 directly dephosphorylates Cdc2-Tyr15, and its cellular concentration rises as cells approach mitosis, making it rate-limiting for mitotic timing.

"p80cdc25 encodes a phosphate that acts by directly dephosphorylating the Tyr-15 residue of p34cdc2"

PMID:18272791

Activation of Srk1 by the mitogen-activated protein kinase Sty1/Spc1 precedes its dissociation from the kinase and signals its degradation.

Stress-activated Srk1 negatively regulates the cell cycle by inhibiting Cdc25; Cdc25 is localized to nucleus and cytosol.

"activation of Srk1 kinase, which negatively regulates cell cycle progression by inhibiting Cdc25"

PMID:22665807

Multisite phosphoregulation of Cdc25 activity refines the mitotic entrance and exit switches.

Cdk1 hyperphosphorylates and catalytically activates Cdc25 in a positive feedback loop driving the abrupt G2/M switch; Clp1/Cdc14 reverses this at exit.

"Cdc25 hyperphosphorylation by Cdk1 governs Cdc25 catalytic activation, the precision of mitotic entry, and unvarying cell length"

PMID:25492408

Meiotic nuclear movements in fission yeast are regulated by the transcription factor Mei4 downstream of a Cds1-dependent replication checkpoint pathway.

Cdc25 expression (driven by Mei4) activates CDK and is essential for triggering meiotic nuclear divisions, acting downstream of the replication checkpoint.

"Mei4 is also required for the expression of phosphatase Cdc25, which activates cyclin-dependent kinase (CDK), and is thereby essential for triggering meiotic nuclear divisions"

PMID:2665944

Regulation of p34cdc2 protein kinase during mitosis.

The cdc25+ gene product activates p34cdc2 to initiate mitosis; mitotic kinase activity also requires cyclin (cdc13).

"the cdc25+ gene product activating the p34cdc2 protein kinase leading to mitotic initiation"

PMID:28479325

Size-Dependent Expression of the Mitotic Activator Cdc25 Suggests a Mechanism of Size Control in Fission Yeast.

Cell size in fission yeast is regulated by size-dependent expression of Cdc25: Cdc25 concentration rises as cells grow, triggering division at a threshold.

"cdc25 transcript levels are regulated such that smaller cells express less Cdc25 and larger cells express more Cdc25, creating an increasing concentration of Cdc25 as cells grow and providing a mechanism for cells to trigger cell division when they reach a threshold concentration of Cdc25"

PMID:3955656

cdc25+ functions as an inducer in the mitotic control of fission yeast.

cdc25+ is required to initiate mitosis and acts as a dosage-dependent inducer that counteracts the mitotic inhibitor wee1+.

"increased cdc25+ expression causes mitosis to initiate at a reduced cell size. This shows that cdc25+ functions as a dosage-dependent inducer in mitotic control"

PMID:9042863

Cdc2 tyrosine phosphorylation is required for the DNA damage checkpoint in fission yeast.

The G2 DNA damage checkpoint depends on inhibitory Cdc2-Tyr15 phosphorylation; irradiation reduces the rate of Cdc2 tyrosine dephosphorylation carried out mainly by Cdc25.

"the rate of Cdc2 tyrosine dephosphorylation is reduced by irradiation. This result implicates regulation of Cdc2 tyrosine dephosphorylation, mainly carried out by the Cdc25 tyrosine phosphatase"

PMID:9278510

Cdc25 mitotic inducer targeted by chk1 DNA damage checkpoint kinase.

Cdc25 (not Wee1) is the target of the Chk1 DNA damage checkpoint kinase; Chk1 associates with and phosphorylates Cdc25.

"These findings identify Cdc25, but not Wee1, as a target of the DNA damage checkpoint"

PMID:9774107

Replication checkpoint requires phosphorylation of the phosphatase Cdc25 by Cds1 or Chk1.

Chk1 and Cds1 redundantly phosphorylate Cdc25 (including Ser99, Ser192, Ser359) to promote 14-3-3 binding, preventing Cdc25 from activating Cdc2 at the replication checkpoint.

"Phosphorylation of Cdc25 promotes its binding to 14-3-3 proteins, preventing it from activating Cdc2."

Suggested Experiments

Experiment: Phosphoproteomic and substrate-trapping (catalytically inactive Cys480Ser) assays to define the full in vivo substrate repertoire of Cdc25 beyond Cdc2-Tyr15.

Experiment: Quantitative live-cell imaging of endogenously tagged Cdc25 to measure how its nuclear/cytoplasmic concentration changes with cell size and across checkpoint activation, testing the threshold-concentration size-control model.

Experiment: Separation-of-function 14-3-3 binding-site mutants combined with forced nuclear or cytoplasmic targeting to dissect whether checkpoint inhibition of Cdc25 is driven primarily by relocalization or by intrinsic activity changes.

📚 Additional Documentation

Notes

(cdc25-notes.md)

cdc25 (S. pombe) review notes

UniProt: P06652 (MPIP_SCHPO), gene SPAC24H6.05. "M-phase inducer phosphatase" / p80cdc25.
596 aa, Rhodanese-like catalytic domain (429-533), active-site phosphocysteine intermediate at Cys480.

Core function

cdc25 is the protein-tyrosine phosphatase that dephosphorylates Cdc2 (CDK1) on Tyr15, the rate-limiting
step triggering mitotic entry. It is the positive counterpart of the Wee1/Mik1 tyrosine kinases.

PMID:3955656 — also notes it "functions to counteract the activity of the mitotic inhibitor wee1+".
PMID:1756737. C-terminal 23 kDa is the active domain; GST-cdc25 dephosphorylates pNPP and phospho-casein; "Reaction requirements and inhibitor sensitivities were the same as those of phosphotyrosine phosphatases (PTPases)"; "Mutation of the cdc25 Cys480 codon ... abolished the phosphatase activity". → catalytic, active-site cysteine confirmed.
PMID:1703321 — human PTPase complements p80cdc25.
PMID:1819507 (note: "phosphate" is a typo for phosphatase in source). Level of p80cdc25 rises as cells approach mitosis; timing of mitosis sensitive to cdc25+ dosage.
PMID:2665944.

EC 3.1.3.48 (protein-tyrosine-phosphatase). MF: protein tyrosine phosphatase activity (GO:0004725) — core, strongly supported.
GO:0004721 phosphoprotein phosphatase activity (IDA, PMID:22665807) is a broader parent; the IDA in that paper is about Cdk1/Clp1 phosphoregulation of Cdc25 — keep but the tyrosine-specific term is more informative.

Cell size control / positive regulation of G2/M

PMID:28479325 and "smaller cells express less Cdc25 and larger cells express more Cdc25, creating an increasing concentration of Cdc25 as cells grow and providing a mechanism for cells to trigger cell division when they reach a threshold concentration of Cdc25." This is mitotic G2 cell size control checkpoint (GO:0031569, IMP). Cell-size regulation (GO:0008361, NAS) is the older keyword-based statement.
PMID:22665807 — Cdk1-Cdc25 positive feedback; Clp1/Cdc14 reverses it at mitotic exit.

Checkpoint regulation (Cdc25 is the TARGET, inhibited by checkpoint kinases)

PMID:9278510; "Cdc25 associated with Chk1 in vivo and was phosphorylated when copurified in Chk1 complexes." → response to mitotic G2 DNA damage checkpoint signaling (GO:0072435, IMP); protein binding with chk1 (SPCC1259.13).
PMID:9774107; "Chk1 functions redundantly with the kinase Cds1 at the replication checkpoint and ... both kinases phosphorylate Cdc25 on the same sites, which include serine residues at positions 99, 192 and 359." IPI partners: cds1 (SPAC17A2.13c) and rad24 14-3-3 (SPAC8E11.02c).
PMID:10523629; wild-type Cdc25 shuttles (nuclear accumulation with leptomycin B); Rad24 (14-3-3) overproduction → cytoplasmic. IPI partner rad24 (SPAC8E11.02c).
PMID:9042863 — PomBase used this for PTP activity IMP.
PMID:15297457 intra-S DNA damage checkpoint: Rad3-Cds1 pathway targets Cdc2; Cdc25 IMP for GO:0031573.
PMID:15629716 Localization: cytoplasm + nucleus (IDA).
PMID:18272791. IDA nucleus + cytosol.

Localization

Cytoplasm + nucleus, shuttling; highest nuclear in G2. PMID:15629716, PMID:10523629, PMID:28479325.
HDA cytosol (PMID:16823372 ORFeome global localization).
PMID:1500423 is the MAMMALIAN cdc25 (nuclear), not S. pombe — annotated to P06652 by PomBase as orthologous support for nucleus. Keep but note it is heterologous evidence.

Meiosis (non-core, but genuine)

cdc25 is also required for meiotic nuclear divisions (meiosis I onset), via the same Cdc2-Tyr15 dephosphorylation, downstream of the meiotic transcription factor Mei4.
- PMID:17804800. Mei4 activates cdc25+ transcription. → GO:0110044 regulation of cell cycle switching, mitotic to meiotic (IMP) and GO:0110032 positive regulation of G2/MI transition of meiotic cell cycle.
- PMID:25492408; "Cdc25 triggers entry to nuclear divisions downstream of the replication checkpoint independently of Mei4." → GO:0110032 (IMP).

These meiotic roles are the SAME biochemical activity (Cdc2-Y15 dephosphorylation) deployed in the meiotic cell cycle; they are real (not SPKW keyword artifacts) but are not the single core function — keep as non-core.

Protein binding (IPI) — replace bare protein binding where possible

PMID:9278510 with chk1 (SPCC1259.13): Cdc25 is a substrate/binding partner of the Chk1 checkpoint kinase. Could be modeled as kinase binding, but the experimental finding is being a checkpoint-kinase target.
PMID:9774107 with cds1 (SPAC17A2.13c) AND rad24 14-3-3 (SPAC8E11.02c): substrate of Cds1; binds 14-3-3.
PMID:10523629 with rad24 (SPAC8E11.02c): 14-3-3 binding.
PMID:11812792 with suc1/p13suc1 (SPBC1734.14c): this NMR paper is about p13suc1/CKS; the cdc25 IPI here is weak/peripheral. The paper does not actually characterize a Cdc25-Suc1 interaction in detail — mark as over-annotated / undecided (paper is about suc1 structure, not cdc25).

GO curation guideline: avoid bare "protein binding" (GO:0005515). For the 14-3-3 interactions, GO:0071889 (14-3-3 protein binding) is the informative term. For chk1/cds1 (these kinases act ON cdc25), the relationship is best captured by the BP checkpoint terms rather than a generic MF; suggest MODIFY rad24 IPIs to 14-3-3 protein binding, and mark the others as over-annotated (uninformative protein binding).

📄 View Raw YAML

id: P06652
gene_symbol: cdc25
product_type: PROTEIN
status: DRAFT
taxon:
  id: NCBITaxon:284812
  label: Schizosaccharomyces pombe (strain 972 / ATCC 24843)
description: >-
  Cdc25 (p80cdc25, M-phase inducer phosphatase) is the protein tyrosine phosphatase
  that triggers entry into mitosis in fission yeast. It dephosphorylates the
  cyclin-dependent kinase Cdc2 (CDK1) on the inhibitory residue Tyr15, thereby
  activating the Cdc2-cyclin B (Cdc13) kinase; this Tyr15 dephosphorylation is the
  rate-limiting step for the G2/M transition. Cdc25 is the positive counterpart of
  the inhibitory Wee1/Mik1 tyrosine kinases, and it acts as a dosage-dependent
  mitotic inducer: increasing Cdc25 concentration as cells grow couples cell size to
  the timing of division. Catalysis uses a rhodanese-fold catalytic domain with an
  essential active-site cysteine (Cys480) that forms a phosphocysteine intermediate.
  Cdc25 is the principal target through which the DNA replication and DNA damage
  checkpoints, and the stress-activated Sty1/Srk1 pathway, restrain mitotic entry:
  the checkpoint kinases Chk1, Cds1 and Srk1 phosphorylate Cdc25, creating 14-3-3
  (Rad24/Rad25) binding sites that promote its nuclear exclusion and inhibit its
  ability to activate Cdc2. Cdc25 shuttles between cytoplasm and nucleus, with
  nuclear accumulation highest in G2. The same Cdc2-Tyr15 dephosphorylating activity
  is also required for meiotic nuclear divisions, where cdc25 expression is driven by
  the meiotic transcription factor Mei4.
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Cdc25 is partly nuclear; it shuttles between cytoplasm and nucleus, with
      nuclear accumulation highest in G2 where it must access its substrate Cdc2.
      Nuclear localization is supported by direct S. pombe experimental data.
    action: ACCEPT
    reason: >-
      Phylogenetic inference is consistent with direct S. pombe localization data
      showing Cdc25 in both nucleus and cytoplasm.
    supported_by:
    - reference_id: PMID:10523629
      supporting_text: >-
        wild-type Cdc25, which localized to both the cytoplasm and the nucleus.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Cdc25 is present in the cytoplasm as well as the nucleus; checkpoint and
      stress signaling drive 14-3-3-dependent cytoplasmic accumulation to sequester
      Cdc25 away from its nuclear substrate.
    action: ACCEPT
    reason: >-
      Supported by phylogenetic inference and corroborated by direct S. pombe
      localization data.
    supported_by:
    - reference_id: PMID:15629716
      supporting_text: >-
        Phosphorylation by Srk1 causes Cdc25 to bind to Rad24, a 14-3-3 protein
        family member, and accumulation of Cdc25 in the cytoplasm.
      reference_section_type: ABSTRACT
- term:
    id: GO:0000086
    label: G2/M transition of mitotic cell cycle
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Cdc25 acts at the G2/M transition by dephosphorylating Cdc2-Tyr15 to trigger
      mitotic entry. This is a core process, though the directional term positive
      regulation of G2/M transition (GO:0010971) more precisely captures Cdc25's
      activating role.
    action: ACCEPT
    reason: >-
      Cdc25 is the founding mitotic inducer acting at G2/M; well supported by
      classical genetics.
    supported_by:
    - reference_id: PMID:3955656
      supporting_text: >-
        the cdc25+ gene function is required to initiate
      reference_section_type: ABSTRACT
- term:
    id: GO:0010971
    label: positive regulation of G2/M transition of mitotic cell cycle
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Core biological process. Cdc25 is a dosage-dependent positive regulator of
      mitotic entry: increased Cdc25 advances mitosis to a smaller cell size, and it
      counteracts the inhibitory Wee1 kinase.
    action: ACCEPT
    reason: >-
      This is the central, experimentally established role of Cdc25 as the mitotic
      inducer counteracting Wee1.
    supported_by:
    - reference_id: PMID:3955656
      supporting_text: >-
        increased cdc25+ expression causes mitosis to initiate at a reduced cell
        size. This shows that cdc25+ functions as a dosage-dependent inducer in
        mitotic control
      reference_section_type: ABSTRACT
- term:
    id: GO:0110032
    label: positive regulation of G2/MI transition of meiotic cell cycle
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Cdc25 also drives the meiotic G2/MI transition using the same Cdc2-Tyr15
      dephosphorylation; its expression in meiosis is induced by Mei4. This is a
      genuine but non-core role relative to its central mitotic function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Meiotic involvement is experimentally supported (not an SPKW keyword artifact),
      but it is a deployment of the same activity in meiosis rather than the primary
      mitotic function.
    supported_by:
    - reference_id: PMID:17804800
      supporting_text: >-
        Forced dephosphorylation of Cdc2p on tyrosine-15 thus induced meiosis I in
        mei4 mutant cells without a delay
      reference_section_type: ABSTRACT
- term:
    id: GO:0004725
    label: protein tyrosine phosphatase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Core molecular function. Cdc25 is a protein tyrosine phosphatase (EC 3.1.3.48)
      that dephosphorylates Cdc2-Tyr15; the IEA mapping is fully consistent with
      direct experimental evidence.
    action: ACCEPT
    reason: >-
      Strongly supported by direct biochemical and genetic data demonstrating
      tyrosine phosphatase activity toward Cdc2.
    supported_by:
    - reference_id: PMID:1756737
      supporting_text: >-
        GST-cdc25) caused tyrosyl dephosphorylation and activation of
        immunoprecipitated p34cdc2
      reference_section_type: ABSTRACT
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Nuclear localization mapped from UniProt Subcellular Location vocabulary;
      consistent with direct S. pombe data showing Cdc25 accumulates in the nucleus,
      highest in G2.
    action: ACCEPT
    reason: Concordant with experimental localization evidence.
    supported_by:
    - reference_id: PMID:10523629
      supporting_text: >-
        wild-type Cdc25, which localized to both the cytoplasm and the nucleus.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Cytoplasmic localization mapped from UniProt Subcellular Location vocabulary;
      consistent with the experimentally observed cytoplasm/nucleus distribution and
      14-3-3-driven cytoplasmic sequestration.
    action: ACCEPT
    reason: Concordant with experimental localization evidence.
    supported_by:
    - reference_id: PMID:10523629
      supporting_text: >-
        wild-type Cdc25, which localized to both the cytoplasm and the nucleus.
      reference_section_type: ABSTRACT
- term:
    id: GO:1902751
    label: positive regulation of cell cycle G2/M phase transition
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO term that is essentially equivalent to GO:0010971 (positive
      regulation of G2/M transition of mitotic cell cycle), which is more specific
      and already directly supported. Redundant with the mitotic-specific term.
    action: MODIFY
    reason: >-
      The mitotic-specific child term GO:0010971 is preferred over this more general
      cell cycle phase transition term.
    proposed_replacement_terms:
    - id: GO:0010971
      label: positive regulation of G2/M transition of mitotic cell cycle
    supported_by:
    - reference_id: PMID:3955656
      supporting_text: >-
        cdc25+ functions as a dosage-dependent inducer in mitotic control
      reference_section_type: ABSTRACT
- term:
    id: GO:0004725
    label: protein tyrosine phosphatase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      Sequence-similarity transfer of protein tyrosine phosphatase activity;
      redundant with the strong direct IDA evidence in S. pombe but correct.
    action: ACCEPT
    reason: Correct function, directly demonstrated experimentally in S. pombe.
    supported_by:
    - reference_id: PMID:1756737
      supporting_text: >-
        cdc25 proteins directly dephosphorylate and activate p34cdc2 kinase to
        induce M-phase
      reference_section_type: ABSTRACT
- term:
    id: GO:0031569
    label: mitotic G2 cell size control checkpoint signaling
  evidence_type: IMP
  original_reference_id: PMID:28479325
  qualifier: involved_in
  review:
    summary: >-
      Size-dependent expression of Cdc25 provides a cell-size control mechanism:
      smaller cells make less Cdc25 and larger cells more, so cells trigger division
      when Cdc25 reaches a threshold concentration. A bona fide core-related role in
      coupling cell size to mitotic entry.
    action: ACCEPT
    reason: >-
      Directly supported by the cited study demonstrating size-dependent Cdc25
      expression as a size-control mechanism.
    supported_by:
    - reference_id: PMID:28479325
      supporting_text: >-
        cdc25 transcript levels are regulated such that smaller cells express less
        Cdc25 and larger cells express more Cdc25, creating an increasing
        concentration of Cdc25 as cells grow and providing a mechanism for cells to
        trigger cell division when they reach a threshold concentration of Cdc25
      reference_section_type: ABSTRACT
- term:
    id: GO:0004725
    label: protein tyrosine phosphatase activity
  evidence_type: IMP
  original_reference_id: PMID:9042863
  qualifier: enables
  review:
    summary: >-
      This paper shows the DNA damage checkpoint G2 arrest depends on inhibitory
      Cdc2-Tyr15 phosphorylation and that the rate of Cdc2 tyrosine dephosphorylation
      (mainly via Cdc25) is reduced by irradiation. It supports Cdc25 acting as the
      Cdc2 tyrosine dephosphorylating activity in the checkpoint context but is not a
      direct enzymatic assay of Cdc25 PTP activity. The molecular function itself is
      better and more directly supported by IDA references.
    action: ACCEPT
    reason: >-
      Function is correct (Cdc25 is the Cdc2 tyrosine phosphatase) and the cited work
      is consistent, though this is genetic/indirect; stronger IDA evidence exists.
    supported_by:
    - reference_id: PMID:9042863
      supporting_text: >-
        the rate of Cdc2 tyrosine dephosphorylation is reduced by irradiation. This
        result implicates regulation of Cdc2 tyrosine dephosphorylation, mainly
        carried out by the Cdc25 tyrosine phosphatase
      reference_section_type: ABSTRACT
- term:
    id: GO:0110044
    label: regulation of cell cycle switching, mitotic to meiotic cell cycle
  evidence_type: IMP
  original_reference_id: PMID:17804800
  qualifier: involved_in
  review:
    summary: >-
      cdc25 is a key Mei4 target controlling entry into meiosis I; forced Cdc2-Tyr15
      dephosphorylation bypasses the mei4 arrest. Cdc25 thus contributes to the
      transition into the meiotic program. A genuine non-core meiotic role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally supported meiotic involvement, but secondary to the core mitotic
      function.
    supported_by:
    - reference_id: PMID:17804800
      supporting_text: >-
        cdc25+ is an important target of Mei4p in control of entry into meiosis I
      reference_section_type: ABSTRACT
- term:
    id: GO:0004721
    label: phosphoprotein phosphatase activity
  evidence_type: IDA
  original_reference_id: PMID:22665807
  qualifier: enables
  review:
    summary: >-
      Broad parent term for phosphatase activity. Cdc25 is specifically a protein
      tyrosine phosphatase (GO:0004725); the more specific term should be used. The
      cited paper concerns Cdk1/Clp1 phosphoregulation of Cdc25 catalytic activation
      rather than a new substrate specificity.
    action: MODIFY
    reason: >-
      The specific tyrosine phosphatase term is more informative than the general
      phosphoprotein phosphatase activity term.
    proposed_replacement_terms:
    - id: GO:0004725
      label: protein tyrosine phosphatase activity
    supported_by:
    - reference_id: PMID:22665807
      supporting_text: >-
        Cdc25 hyperphosphorylation by Cdk1 governs Cdc25 catalytic activation
      reference_section_type: ABSTRACT
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:18272791
  qualifier: is_active_in
  review:
    summary: >-
      Direct S. pombe evidence; Srk1 negatively regulates the cycle by inhibiting
      Cdc25 and driving its nucleus-to-cytoplasm relocation, consistent with a
      nuclear pool of Cdc25 acting on Cdc2.
    action: ACCEPT
    reason: Supported by direct experimental localization in S. pombe.
    supported_by:
    - reference_id: PMID:18272791
      supporting_text: >-
        activation of Srk1 kinase, which negatively regulates cell cycle progression
        by inhibiting Cdc25
      reference_section_type: ABSTRACT
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:18272791
  qualifier: is_active_in
  review:
    summary: >-
      Cytosolic pool of Cdc25 consistent with Srk1/14-3-3-dependent cytoplasmic
      sequestration. Direct S. pombe evidence.
    action: ACCEPT
    reason: Supported by direct experimental localization in S. pombe.
    supported_by:
    - reference_id: PMID:18272791
      supporting_text: >-
        activation of Srk1 kinase, which negatively regulates cell cycle progression
        by inhibiting Cdc25
      reference_section_type: ABSTRACT
- term:
    id: GO:0004725
    label: protein tyrosine phosphatase activity
  evidence_type: IDA
  original_reference_id: PMID:1703321
  qualifier: enables
  review:
    summary: >-
      Direct demonstration that Tyr15 dephosphorylation activates the Cdc2-cyclin
      complex and that a human PTPase substitutes for p80cdc25, reinforcing the
      tyrosine phosphatase identity of Cdc25. Core molecular function.
    action: ACCEPT
    reason: Direct evidence for tyrosine phosphatase activity in the Cdc2 activation pathway.
    supported_by:
    - reference_id: PMID:1703321
      supporting_text: >-
        dephosphorylation of Tyr15 triggered activation of the pp34-cyclin complex
        from fission yeast, that a human protein-tyrosine phosphatase can catalyze
        this event both in vitro and in vivo
      reference_section_type: ABSTRACT
- term:
    id: GO:0010971
    label: positive regulation of G2/M transition of mitotic cell cycle
  evidence_type: IMP
  original_reference_id: PMID:1703321
  qualifier: involved_in
  review:
    summary: >-
      Cdc25 (and the complementing human PTPase) positively regulates mitotic entry
      via Cdc2-Tyr15 dephosphorylation. Core process, well supported.
    action: ACCEPT
    reason: Directly supports Cdc25's positive role in the G2/M transition.
    supported_by:
    - reference_id: PMID:1703321
      supporting_text: >-
        The complementary DNA that encoded the tyrosine phosphatase replaced the mitotic
        activator p80cdc25, closely associating the cdc25(+)-activating pathway with tyrosine
        dephosphorylation of pp34.
      reference_section_type: ABSTRACT
- term:
    id: GO:0072435
    label: response to mitotic G2 DNA damage checkpoint signaling
  evidence_type: IMP
  original_reference_id: PMID:9278510
  qualifier: involved_in
  review:
    summary: >-
      Cdc25 is the direct target of the Chk1 DNA damage checkpoint kinase (and not
      Wee1); Chk1 associates with and phosphorylates Cdc25 to restrain mitosis after
      damage. Core checkpoint-related function as the regulated node.
    action: ACCEPT
    reason: >-
      Strong genetic and biochemical evidence that Cdc25 is the effector target of
      the G2 DNA damage checkpoint.
    supported_by:
    - reference_id: PMID:9278510
      supporting_text: >-
        These findings identify Cdc25, but not Wee1, as a target of the DNA damage
        checkpoint
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9278510
  qualifier: enables
  review:
    summary: >-
      Bare protein binding referring to the Cdc25-Chk1 interaction (Chk1 is the
      checkpoint kinase acting on Cdc25). Uninformative as a molecular function; the
      functional content is captured by the DNA damage checkpoint BP term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per curation guidelines, bare protein binding is uninformative; the relevant
      biology (Cdc25 as a Chk1 substrate/target) is better represented by checkpoint
      process terms.
    supported_by:
    - reference_id: PMID:9278510
      supporting_text: >-
        Cdc25 associated with Chk1 in vivo and was phosphorylated when copurified in
        Chk1 complexes
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9774107
  qualifier: enables
  review:
    summary: >-
      Bare protein binding covering the Cds1/Chk1 and Rad24 (14-3-3) interactions.
      The 14-3-3 interaction is functionally important and is better represented by
      the specific term 14-3-3 protein binding (GO:0071889).
    action: MODIFY
    reason: >-
      Replace uninformative protein binding with the specific 14-3-3 protein binding
      term that captures the checkpoint-relevant interaction with Rad24.
    proposed_replacement_terms:
    - id: GO:0071889
      label: 14-3-3 protein binding
    supported_by:
    - reference_id: PMID:9774107
      supporting_text: >-
        Phosphorylation of Cdc25 promotes its binding to 14-3-3 proteins, preventing
        it from activating Cdc2
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10523629
  qualifier: enables
  review:
    summary: >-
      Bare protein binding referring to the Cdc25-Rad24 (14-3-3) interaction that
      mediates checkpoint-dependent nuclear exclusion. The specific term 14-3-3
      protein binding is more informative.
    action: MODIFY
    reason: >-
      Replace uninformative protein binding with 14-3-3 protein binding, capturing the
      functionally characterized Rad24 interaction.
    proposed_replacement_terms:
    - id: GO:0071889
      label: 14-3-3 protein binding
    supported_by:
    - reference_id: PMID:10523629
      supporting_text: >-
        Nuclear exclusion of wild-type Cdc25 was observed upon overproduction of Rad
        24, one of the two fission yeast 14-3-3 proteins
      reference_section_type: ABSTRACT
- term:
    id: GO:0110032
    label: positive regulation of G2/MI transition of meiotic cell cycle
  evidence_type: IMP
  original_reference_id: PMID:25492408
  qualifier: involved_in
  review:
    summary: >-
      Cdc25 triggers entry into meiotic nuclear divisions by activating CDK,
      downstream of the replication checkpoint and independently of Mei4 once
      expressed. A real non-core meiotic role using the core Cdc2-activating activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally supported meiotic role, secondary to the core mitotic function.
    supported_by:
    - reference_id: PMID:25492408
      supporting_text: >-
        Mei4 is also required for the expression of phosphatase Cdc25, which
        activates cyclin-dependent kinase (CDK), and is thereby essential for
        triggering meiotic nuclear divisions
      reference_section_type: INTRODUCTION
- term:
    id: GO:0004725
    label: protein tyrosine phosphatase activity
  evidence_type: IDA
  original_reference_id: PMID:1464318
  qualifier: enables
  review:
    summary: >-
      This paper characterizes Pyp3 as a second PTPase that cooperates with p80cdc25
      to dephosphorylate Cdc2-Tyr15; it confirms cdc25 is a protein tyrosine
      phosphatase but the direct enzymatic data are on Pyp3, not Cdc25. The MF
      assignment to Cdc25 is correct but more directly supported by other references.
    action: ACCEPT
    reason: >-
      Function is correct (Cdc25 is the major Cdc2 PTPase); strongest direct evidence
      is in other references.
    supported_by:
    - reference_id: PMID:1464318
      supporting_text: >-
        the actions of the p107wee1 tyrosine kinase and p80cdc25 protein tyrosine
        phosphatase (PTPase)
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11812792
  qualifier: enables
  review:
    summary: >-
      Bare protein binding linked to an NMR structural study of p13suc1/CKS. The
      paper is about Suc1 structure and does not substantively characterize a
      functional Cdc25-Suc1 interaction; uninformative and peripheral for Cdc25.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding is uninformative, and the cited reference is a Suc1
      structural study rather than a characterization of a Cdc25 interaction.
    supported_by:
    - reference_id: PMID:11812792
      supporting_text: >-
        Cyclin-dependent kinase subunit (CKS) proteins bind to cyclin-dependent
        kinases and target various proteins to phosphorylation and proteolysis
        during cell division
      reference_section_type: ABSTRACT
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:15629716
  qualifier: is_active_in
  review:
    summary: >-
      Direct S. pombe evidence that Cdc25 localizes to the nucleus (and cytoplasm),
      with Srk1/14-3-3 controlling its compartmentalization. Nuclear pool is where
      Cdc25 activates Cdc2.
    action: ACCEPT
    reason: Supported by direct experimental localization in S. pombe.
    supported_by:
    - reference_id: PMID:15629716
      supporting_text: >-
        Phosphorylation by Srk1 causes Cdc25 to bind to Rad24, a 14-3-3 protein
        family member, and accumulation of Cdc25 in the cytoplasm.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:15629716
  qualifier: is_active_in
  review:
    summary: >-
      Direct S. pombe evidence for a cytoplasmic pool of Cdc25, increased upon Srk1
      phosphorylation and 14-3-3 (Rad24) binding.
    action: ACCEPT
    reason: Supported by direct experimental localization in S. pombe.
    supported_by:
    - reference_id: PMID:15629716
      supporting_text: >-
        Phosphorylation by Srk1 causes Cdc25 to bind to Rad24, a 14-3-3 protein
        family member, and accumulation of Cdc25 in the cytoplasm.
      reference_section_type: ABSTRACT
- term:
    id: GO:0031573
    label: mitotic intra-S DNA damage checkpoint signaling
  evidence_type: IMP
  original_reference_id: PMID:15297457
  qualifier: involved_in
  review:
    summary: >-
      The intra-S DNA damage checkpoint (Rad3-Cds1 pathway) acts on Cdc2, with Cdc25
      regulation contributing to S-phase slowing. Cdc25 participates as the regulated
      Cdc2 activator. Keep as a checkpoint-related role.
    action: ACCEPT
    reason: >-
      Cdc25 is part of the intra-S checkpoint response acting through Cdc2 regulation.
    supported_by:
    - reference_id: PMID:15297457
      supporting_text: >-
        a major downstream target of this pathway is the cyclin-dependent kinase,
        Cdc2
      reference_section_type: ABSTRACT
- term:
    id: GO:0010971
    label: positive regulation of G2/M transition of mitotic cell cycle
  evidence_type: IMP
  original_reference_id: PMID:2665944
  qualifier: involved_in
  review:
    summary: >-
      The cdc25+ gene product activates the p34cdc2 protein kinase to initiate
      mitosis, the canonical positive regulation of the G2/M transition. Core process.
    action: ACCEPT
    reason: Directly supports Cdc25's positive role in mitotic initiation.
    supported_by:
    - reference_id: PMID:2665944
      supporting_text: >-
        the cdc25+ gene product activating the p34cdc2 protein kinase leading to
        mitotic initiation
      reference_section_type: ABSTRACT
- term:
    id: GO:0004725
    label: protein tyrosine phosphatase activity
  evidence_type: IDA
  original_reference_id: PMID:1756737
  qualifier: enables
  review:
    summary: >-
      Definitive demonstration that p80cdc25 is the tyrosine phosphatase that
      dephosphorylates and activates p34cdc2, with active-site Cys480 essential.
      Core molecular function with the strongest direct evidence.
    action: ACCEPT
    reason: >-
      Direct biochemical evidence (tyrosyl dephosphorylation, PTPase properties,
      catalytic cysteine mutation) for Cdc25 PTP activity.
    supported_by:
    - reference_id: PMID:1756737
      supporting_text: >-
        Mutation of the cdc25 Cys480 codon, corresponding to an essential cysteine in
        the active site of PTPases, abolished the phosphatase activity of GST-cdc25
      reference_section_type: ABSTRACT
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: HDA
  original_reference_id: PMID:16823372
  qualifier: is_active_in
  review:
    summary: >-
      High-throughput YFP-based localization places Cdc25 in the cytosol, consistent
      with its known cytoplasmic/nuclear shuttling. Lower-resolution evidence but
      concordant with focused studies.
    action: ACCEPT
    reason: >-
      Genome-wide localization data consistent with the experimentally established
      cytoplasm/nucleus distribution.
    supported_by:
    - reference_id: PMID:15629716
      supporting_text: >-
        accumulation of Cdc25 in the cytoplasm.
      reference_section_type: ABSTRACT
- term:
    id: GO:0008361
    label: regulation of cell size
  evidence_type: NAS
  original_reference_id: GO_REF:0000051
  qualifier: involved_in
  review:
    summary: >-
      Cdc25 regulates the cell size at which division occurs (dosage-dependent
      mitotic inducer; size-dependent expression). The more specific term mitotic G2
      cell size control checkpoint signaling (GO:0031569), already annotated with IMP,
      better captures the mechanism.
    action: MODIFY
    reason: >-
      A more specific, experimentally supported size-control checkpoint term is
      available; replace the general cell-size term.
    proposed_replacement_terms:
    - id: GO:0031569
      label: mitotic G2 cell size control checkpoint signaling
    supported_by:
    - reference_id: PMID:28479325
      supporting_text: >-
        smaller cells express less Cdc25 and larger cells express more Cdc25
      reference_section_type: ABSTRACT
- term:
    id: GO:0004725
    label: protein tyrosine phosphatase activity
  evidence_type: IDA
  original_reference_id: PMID:1819507
  qualifier: enables
  review:
    summary: >-
      p80cdc25 directly dephosphorylates Tyr-15 of p34cdc2; supports the core
      tyrosine phosphatase activity. Concordant with other direct evidence.
    action: ACCEPT
    reason: Direct evidence for Cdc25-mediated Cdc2-Tyr15 dephosphorylation.
    supported_by:
    - reference_id: PMID:1819507
      supporting_text: >-
        p80cdc25 encodes a phosphate that acts by directly dephosphorylating the
        Tyr-15 residue of p34cdc2
      reference_section_type: ABSTRACT
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:1500423
  qualifier: is_active_in
  review:
    summary: >-
      This study characterizes the MAMMALIAN cdc25 protein in nontransformed
      fibroblasts (nuclear during interphase), not the S. pombe protein. The
      localization is therefore heterologous/orthology-based support rather than
      direct S. pombe evidence, but it is consistent with the native nuclear pool.
    action: ACCEPT
    reason: >-
      Nuclear localization is consistent with direct S. pombe data; however the cited
      reference is mammalian, so it provides only orthologous (ISS-like) support.
    supported_by:
    - reference_id: PMID:1500423
      supporting_text: >-
        cdc25 protein is found essentially localized in the nucleus throughout
        interphase and during early prophase
      reference_section_type: ABSTRACT
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:1500423
  qualifier: is_active_in
  review:
    summary: >-
      Mammalian cdc25 redistributes to the cytoplasm around nuclear envelope
      breakdown in fibroblasts; this is heterologous evidence transferred to the S.
      pombe protein. Native S. pombe data independently support a cytoplasmic pool, so
      the term is acceptable though the cited reference is mammalian.
    action: ACCEPT
    reason: >-
      Cytoplasmic localization is supported by direct S. pombe data; the cited
      reference is mammalian and thus orthology-based.
    supported_by:
    - reference_id: PMID:1500423
      supporting_text: >-
        cdc25 proteins are redistributed throughout the cytoplasm
      reference_section_type: ABSTRACT
- term:
    id: GO:0010971
    label: positive regulation of G2/M transition of mitotic cell cycle
  evidence_type: IMP
  original_reference_id: PMID:3955656
  qualifier: involved_in
  review:
    summary: >-
      The original genetic identification of cdc25+ as a dosage-dependent mitotic
      inducer counteracting Wee1. Core process, foundational evidence.
    action: ACCEPT
    reason: >-
      Foundational genetic evidence establishing Cdc25 as the positive regulator of
      mitotic entry.
    supported_by:
    - reference_id: PMID:3955656
      supporting_text: >-
        cdc25+ functions to counteract the activity of the mitotic inhibitor wee1+
      reference_section_type: ABSTRACT
references:
- id: file:interpro/panther/PTHR10828/PTHR10828-review.md
  title: 'PANTHER family review PTHR10828: IBA propagation assessment for cdc25'
  findings: []
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000051
  title: S. pombe keyword mapping
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10523629
  title: DNA damage and replication checkpoints in fission yeast require nuclear exclusion of the Cdc25 phosphatase via 14-3-3 binding.
  findings:
  - statement: >-
      14-3-3 (Rad24/Rad25) binding keeps Cdc25 out of the nucleus and is required for
      DNA damage and replication checkpoint arrest; wild-type Cdc25 localizes to both
      nucleus and cytoplasm and shuttles between them.
    supporting_text: >-
      Nuclear exclusion of wild-type Cdc25 was observed upon overproduction of Rad
      24, one of the two fission yeast 14-3-3 proteins, indicating that one function
      of Rad 24 is to keep Cdc25 out of the nucleus.
    reference_section_type: ABSTRACT
- id: PMID:11812792
  title: Solution NMR study of the monomeric form of p13suc1 protein sheds light on the hinge region determining the affinity for a phosphorylated substrate.
  findings:
  - statement: >-
      Structural study of p13suc1/CKS; does not substantively characterize a Cdc25
      interaction, so the Cdc25 protein-binding annotation derived from it is
      peripheral.
    supporting_text: >-
      Cyclin-dependent kinase subunit (CKS) proteins bind to cyclin-dependent kinases
      and target various proteins to phosphorylation and proteolysis during cell
      division
    reference_section_type: ABSTRACT
- id: PMID:1464318
  title: Pyp3 PTPase acts as a mitotic inducer in fission yeast.
  findings:
  - statement: >-
      p80cdc25 is the major protein tyrosine phosphatase dephosphorylating Cdc2-Tyr15;
      Pyp3 cooperates as a second PTPase.
    supporting_text: >-
      the actions of the p107wee1 tyrosine kinase and p80cdc25 protein tyrosine
      phosphatase (PTPase)
    reference_section_type: ABSTRACT
- id: PMID:1500423
  title: cdc25 is a nuclear protein expressed constitutively throughout the cell cycle in nontransformed mammalian cells.
  findings:
  - statement: >-
      Mammalian cdc25 is nuclear during interphase and redistributes to the cytoplasm
      at nuclear envelope breakdown; this is heterologous evidence relative to S.
      pombe cdc25.
    supporting_text: >-
      cdc25 protein is found essentially localized in the nucleus throughout
      interphase and during early prophase
    reference_section_type: ABSTRACT
- id: PMID:15297457
  title: On the slowing of S phase in response to DNA damage in fission yeast.
  findings:
  - statement: >-
      The Rad3-Cds1 intra-S DNA damage checkpoint acts through Cdc2, the kinase
      whose Tyr15 dephosphorylation is controlled by Cdc25.
    supporting_text: >-
      a major downstream target of this pathway is the cyclin-dependent kinase, Cdc2
    reference_section_type: ABSTRACT
- id: PMID:15629716
  title: Inactivation of the Cdc25 phosphatase by the stress-activated Srk1 kinase in fission yeast.
  findings:
  - statement: >-
      Srk1 (downstream of Sty1/Spc1) inhibits Cdc25 during the normal cycle and under
      non-genotoxic stress by phosphorylating it at the Chk1/Cds1 sites, promoting
      Rad24 (14-3-3) binding and cytoplasmic accumulation.
    supporting_text: >-
      Srk1 interacts with and phosphorylates Cdc25 at the same sites phosphorylated by
      the Chk1 and Cds1 (Chk2) kinases
    reference_section_type: ABSTRACT
- id: PMID:16823372
  title: ORFeome cloning and global analysis of protein localization in the fission yeast Schizosaccharomyces pombe.
  findings: []
- id: PMID:1703321
  title: Complementation of the mitotic activator, p80cdc25, by a human protein-tyrosine phosphatase.
  findings:
  - statement: >-
      Cdc2-Tyr15 dephosphorylation triggers activation of the Cdc2-cyclin complex,
      and a human protein tyrosine phosphatase can substitute for p80cdc25.
    supporting_text: >-
      dephosphorylation of Tyr15 triggered activation of the pp34-cyclin complex from
      fission yeast, that a human protein-tyrosine phosphatase can catalyze this event
      both in vitro and in vivo
    reference_section_type: ABSTRACT
- id: PMID:1756737
  title: p80cdc25 mitotic inducer is the tyrosine phosphatase that activates p34cdc2 kinase in fission yeast.
  findings:
  - statement: >-
      p80cdc25 directly dephosphorylates and activates p34cdc2; the active-site Cys480
      is essential for phosphatase activity, defining Cdc25 as a novel PTPase
      subclass.
    supporting_text: >-
      Mutation of the cdc25 Cys480 codon, corresponding to an essential cysteine in
      the active site of PTPases, abolished the phosphatase activity of GST-cdc25
    reference_section_type: ABSTRACT
- id: PMID:17804800
  title: Mei4p coordinates the onset of meiosis I by regulating cdc25+ in fission yeast.
  findings:
  - statement: >-
      cdc25+ is a key Mei4 target controlling entry into meiosis I; forced Cdc2-Tyr15
      dephosphorylation bypasses the mei4 arrest.
    supporting_text: >-
      Forced dephosphorylation of Cdc2p on tyrosine-15 thus induced meiosis I in mei4
      mutant cells without a delay
    reference_section_type: ABSTRACT
- id: PMID:1819507
  title: cdc25 M-phase inducer.
  findings:
  - statement: >-
      p80cdc25 directly dephosphorylates Cdc2-Tyr15, and its cellular concentration
      rises as cells approach mitosis, making it rate-limiting for mitotic timing.
    supporting_text: >-
      p80cdc25 encodes a phosphate that acts by directly dephosphorylating the Tyr-15
      residue of p34cdc2
    reference_section_type: ABSTRACT
- id: PMID:18272791
  title: Activation of Srk1 by the mitogen-activated protein kinase Sty1/Spc1 precedes its dissociation from the kinase and signals its degradation.
  findings:
  - statement: >-
      Stress-activated Srk1 negatively regulates the cell cycle by inhibiting Cdc25;
      Cdc25 is localized to nucleus and cytosol.
    supporting_text: >-
      activation of Srk1 kinase, which negatively regulates cell cycle progression by
      inhibiting Cdc25
    reference_section_type: ABSTRACT
- id: PMID:22665807
  title: Multisite phosphoregulation of Cdc25 activity refines the mitotic entrance and exit switches.
  findings:
  - statement: >-
      Cdk1 hyperphosphorylates and catalytically activates Cdc25 in a positive
      feedback loop driving the abrupt G2/M switch; Clp1/Cdc14 reverses this at exit.
    supporting_text: >-
      Cdc25 hyperphosphorylation by Cdk1 governs Cdc25 catalytic activation, the
      precision of mitotic entry, and unvarying cell length
    reference_section_type: ABSTRACT
- id: PMID:25492408
  title: Meiotic nuclear movements in fission yeast are regulated by the transcription factor Mei4 downstream of a Cds1-dependent replication checkpoint pathway.
  findings:
  - statement: >-
      Cdc25 expression (driven by Mei4) activates CDK and is essential for triggering
      meiotic nuclear divisions, acting downstream of the replication checkpoint.
    supporting_text: >-
      Mei4 is also required for the expression of phosphatase Cdc25, which activates
      cyclin-dependent kinase (CDK), and is thereby essential for triggering meiotic
      nuclear divisions
    reference_section_type: INTRODUCTION
- id: PMID:2665944
  title: Regulation of p34cdc2 protein kinase during mitosis.
  findings:
  - statement: >-
      The cdc25+ gene product activates p34cdc2 to initiate mitosis; mitotic kinase
      activity also requires cyclin (cdc13).
    supporting_text: >-
      the cdc25+ gene product activating the p34cdc2 protein kinase leading to mitotic
      initiation
    reference_section_type: ABSTRACT
- id: PMID:28479325
  title: Size-Dependent Expression of the Mitotic Activator Cdc25 Suggests a Mechanism of Size Control in Fission Yeast.
  findings:
  - statement: >-
      Cell size in fission yeast is regulated by size-dependent expression of Cdc25:
      Cdc25 concentration rises as cells grow, triggering division at a threshold.
    supporting_text: >-
      cdc25 transcript levels are regulated such that smaller cells express less Cdc25
      and larger cells express more Cdc25, creating an increasing concentration of
      Cdc25 as cells grow and providing a mechanism for cells to trigger cell division
      when they reach a threshold concentration of Cdc25
    reference_section_type: ABSTRACT
- id: PMID:3955656
  title: cdc25+ functions as an inducer in the mitotic control of fission yeast.
  findings:
  - statement: >-
      cdc25+ is required to initiate mitosis and acts as a dosage-dependent inducer
      that counteracts the mitotic inhibitor wee1+.
    supporting_text: >-
      increased cdc25+ expression causes mitosis to initiate at a reduced cell size.
      This shows that cdc25+ functions as a dosage-dependent inducer in mitotic
      control
    reference_section_type: ABSTRACT
- id: PMID:9042863
  title: Cdc2 tyrosine phosphorylation is required for the DNA damage checkpoint in fission yeast.
  findings:
  - statement: >-
      The G2 DNA damage checkpoint depends on inhibitory Cdc2-Tyr15 phosphorylation;
      irradiation reduces the rate of Cdc2 tyrosine dephosphorylation carried out
      mainly by Cdc25.
    supporting_text: >-
      the rate of Cdc2 tyrosine dephosphorylation is reduced by irradiation. This
      result implicates regulation of Cdc2 tyrosine dephosphorylation, mainly carried
      out by the Cdc25 tyrosine phosphatase
    reference_section_type: ABSTRACT
- id: PMID:9278510
  title: Cdc25 mitotic inducer targeted by chk1 DNA damage checkpoint kinase.
  findings:
  - statement: >-
      Cdc25 (not Wee1) is the target of the Chk1 DNA damage checkpoint kinase; Chk1
      associates with and phosphorylates Cdc25.
    supporting_text: >-
      These findings identify Cdc25, but not Wee1, as a target of the DNA damage
      checkpoint
    reference_section_type: ABSTRACT
- id: PMID:9774107
  title: Replication checkpoint requires phosphorylation of the phosphatase Cdc25 by Cds1 or Chk1.
  findings:
  - statement: >-
      Chk1 and Cds1 redundantly phosphorylate Cdc25 (including Ser99, Ser192, Ser359)
      to promote 14-3-3 binding, preventing Cdc25 from activating Cdc2 at the
      replication checkpoint.
    supporting_text: >-
      Phosphorylation of Cdc25 promotes its binding to 14-3-3 proteins, preventing it
      from activating Cdc2.
    reference_section_type: ABSTRACT
core_functions:
- description: >-
    Protein tyrosine phosphatase that dephosphorylates Cdc2 (CDK1) on the inhibitory
    Tyr15 residue, activating the Cdc2-cyclin (Cdc13) kinase to trigger entry into
    mitosis. This is the rate-limiting, dosage-dependent step of the G2/M transition
    and is the positive counterpart to the Wee1/Mik1 inhibitory kinases.
  supported_by:
  - reference_id: PMID:1756737
    supporting_text: >-
      cdc25 proteins directly dephosphorylate and activate p34cdc2 kinase to induce
      M-phase
    reference_section_type: ABSTRACT
  - reference_id: PMID:3955656
    supporting_text: >-
      cdc25+ functions as a dosage-dependent inducer in mitotic control
    reference_section_type: ABSTRACT
  molecular_function:
    id: GO:0004725
    label: protein tyrosine phosphatase activity
  directly_involved_in:
  - id: GO:0010971
    label: positive regulation of G2/M transition of mitotic cell cycle
  - id: GO:0000086
    label: G2/M transition of mitotic cell cycle
  locations:
  - id: GO:0005634
    label: nucleus
  - id: GO:0005829
    label: cytosol
- description: >-
    Central effector node of the DNA replication, DNA damage, and stress-activated
    checkpoints: checkpoint kinases (Chk1, Cds1) and the SAPK-activated Srk1 kinase
    phosphorylate Cdc25 to create 14-3-3 (Rad24/Rad25) binding sites, inhibiting
    Cdc25 and excluding it from the nucleus, thereby delaying mitotic entry until DNA
    is intact and replicated.
  supported_by:
  - reference_id: PMID:9278510
    supporting_text: >-
      These findings identify Cdc25, but not Wee1, as a target of the DNA damage
      checkpoint
    reference_section_type: ABSTRACT
  - reference_id: PMID:10523629
    supporting_text: >-
      14-3-3 binding to Cdc25 is required for fission yeast cells to arrest their cell
      cycle in response to DNA damage and replication blocks.
    reference_section_type: ABSTRACT
  molecular_function:
    id: GO:0071889
    label: 14-3-3 protein binding
  directly_involved_in:
  - id: GO:0072435
    label: response to mitotic G2 DNA damage checkpoint signaling
  - id: GO:0031573
    label: mitotic intra-S DNA damage checkpoint signaling
  locations:
  - id: GO:0005737
    label: cytoplasm
- description: >-
    Size-dependent mitotic inducer: Cdc25 abundance scales with cell size so that the
    rising Cdc25 concentration couples cell growth to the timing of division,
    contributing to cell-size homeostasis at the G2/M transition.
  supported_by:
  - reference_id: PMID:28479325
    supporting_text: >-
      cdc25 transcript levels are regulated such that smaller cells express less Cdc25
      and larger cells express more Cdc25, creating an increasing concentration of
      Cdc25 as cells grow
    reference_section_type: ABSTRACT
  molecular_function:
    id: GO:0004725
    label: protein tyrosine phosphatase activity
  directly_involved_in:
  - id: GO:0031569
    label: mitotic G2 cell size control checkpoint signaling
proposed_new_terms: []
suggested_questions:
- question: >-
    Beyond Cdc2-Tyr15, does Cdc25 have additional physiological substrates in S.
    pombe, or is Cdc2 its sole relevant target?
- question: >-
    How is the balance between the redundant Cdc25 and Pyp3 phosphatases regulated to
    set the precise timing of Tyr15 dephosphorylation?
- question: >-
    What is the relative contribution of nuclear exclusion versus direct catalytic
    inhibition to the 14-3-3-dependent checkpoint silencing of Cdc25?
suggested_experiments:
- description: >-
    Phosphoproteomic and substrate-trapping (catalytically inactive Cys480Ser) assays
    to define the full in vivo substrate repertoire of Cdc25 beyond Cdc2-Tyr15.
- description: >-
    Quantitative live-cell imaging of endogenously tagged Cdc25 to measure how its
    nuclear/cytoplasmic concentration changes with cell size and across checkpoint
    activation, testing the threshold-concentration size-control model.
- description: >-
    Separation-of-function 14-3-3 binding-site mutants combined with forced nuclear
    or cytoplasmic targeting to dissect whether checkpoint inhibition of Cdc25 is
    driven primarily by relocalization or by intrinsic activity changes.

cdc25

Gene Description

Existing Annotations Review

Core Functions

Size-dependent mitotic inducer: Cdc25 abundance scales with cell size so that the rising Cdc25 concentration couples cell growth to the timing of division, contributing to cell-size homeostasis at the G2/M transition.

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Notes

cdc25 (S. pombe) review notes

Core function

Cell size control / positive regulation of G2/M

Checkpoint regulation (Cdc25 is the TARGET, inhibited by checkpoint kinases)

Localization

Meiosis (non-core, but genuine)

Protein binding (IPI) — replace bare protein binding where possible

📄 View Raw YAML